Solid oral dosage forms containing Topiramate (TOP; 2,3:4,5-bis-O-(1-methylethylidene)-beta-D-fructopyranose sulfamate; disclosed in EP 138441) are known (FDA Electronic Orange Book). Topiramate is an anticonvulsant indicated for treating partial onset or primary generalized tonic-clonic seizures in epilepsy, for adjunctive therapy in Lennox-Gaustat syndrome, and migraine. It has also been used to treat bipolar disorder, borderline personality disorder, adjuvant for anti-psychotics, post-traumatic stress disorder, antipsychotic-induced weight gain, and other conditions as is recognized in the relevant art.
Topiramate is susceptible to heat and moisture. Degradation of topiramate is readily detected by changes in physical appearance i.e. discoloration to brown or black, and formation of sulfate ions, which can be measured by standard techniques. A typical solution to overcome this problem is to protect the drug by applying a coating which diminishes the contact of the outside environment with the active ingredient and to use volatile organic solvents while applying the coating.
TOP is dosed at high levels such as 400 mg per day (two 200 mg doses) for the treatment of epilepsy. That upper dose is achieved by dose escalation over a period of 6 weeks. However, young and elderly patients typically experience difficulty in swallowing solid oral dosage forms containing such high doses, especially because of the large amount of excipients included in known dosage forms. Difficulty in swallowing leads to poor patient compliance. Attempts to resolve this problem have lead to the development of oral liquid and injectable formulations. Stability, contamination and inaccurate dosing problems, however, are still associated with such dosage forms, and only tablets or capsules (including a sprinkle capsule) have been approved in the U.S. to date.
Given the high doses of TOP required per tablet, it is difficult to formulate rapidly dispersible solid oral dosage forms with sufficient hardness and friability suitable for storage and handling. Attempts to resolve such problems have been disclosed.
Orodispersible dosage forms disperse or disintegrate in the mouth in a minimal amount of saliva or water. Such dosage forms provide ease of swallowing, accuracy of dosing, and rapid therapeutic action. U.S. Pat. No. 7,749,533 to Fu et al. discloses a dosage form containing granules containing a drug, porous plastic substance, water penetration enhancer, binder and drug. The granules must be compressed in order to create the dosage form. U.S. Pat. No. 4,371,516 to Gregory et al. and U.S. Pat. No. 5,738,875 disclose freeze-dried dosage forms. U.S. Pat. No. 5,178,878 to Wehling et al. discloses a soft-compressed orodispersible dosage form. Effervescent dosage forms and quick release coatings of insoluble microparticles are described in U.S. Pat. Nos. 5,578,322 and 5,607,697. Freeze dried foams and liquids are described in U.S. Pat. No. 4,642,903 and U.S. Pat. No. 5,631,023. Melt-spun dosage forms are described in U.S. Pat. Nos. 4,855,326, 5,380,473 and 5,518,730. U.S. 20070218129 discloses an immediate release dispersible and orodispersible solid pharmaceutical composition having the form of particles with a size lower than 710 μm upon dispersion into water, wherein the formulation is made by wet granulation; however, the disintegration times range from 53 to 60 sec. U.S. Pat. No. 6,471,992, U.S. 2012-0207929 and U.S. 2003-0133975 disclose three-dimensionally printed rapidly dispersing dosage forms.
Topiramate is known to have an extremely bitter taste, which is disadvantageous in orodispersible dosage forms. A major requirement of any such solid form is that it must be palatable to reduce the risk of a patient neglecting to take the medication. In cases where the active ingredient is particularly unpalatable and somewhat unstable, it is difficult to prepare such solid forms, and in addition show good stability and bioavailability.
Taste-masked dosage forms for poorly tasting drugs have been developed. U.S. Pat. No. 6,767,557 to Ulrich suggests a reconstitutable powder containing drug encapsulated in a water insoluble enteric coating. U.S. Pat. No. 6,586,012 and U.S. Pat. No. 6,482,823 to Yu disclose a liquid formulation containing topiramate encapsulated in an acid soluble coating. U.S. 20120207836 to General suggests a film wafer formulation containing drug particles encapsulated in a cationic polyacrylate coating. U.S. 20120076858 to Kolter suggests a rapidly dispersible formulation containing drug particles encapsulated in a cationic polyacrylate coating. U.S. 20120040001 to Koizumi suggests a rapidly dispersible compressed dosage form comprising drug, starch, binder and molding agent. U.S. 20110212171 to Venkatesh discloses an orodispersible dosage form comprising topiramate particles coated with a water insoluble polymer. U.S. 20100285130 to Sanghvi suggests a film formulation comprising a complex of drug and ion exchange resin coated with an ingestible polymer. U.S. 20100278901 and U.S. 20070092553 to Tengler suggests a rapidly dispersible compressed dosage form comprising drug complexed to a resin. U.S. 20070154550 to Arti discloses an acrylate or ethyl cellulose coated powdered form of topiramate. U.S. 20060182796 to Wu discloses an acrylate and enteric polymer coated powder form of topiramate. U.S. 20060159758 to Gandhi a taste-masked formulation containing an acrylate polymer in combination with another polymer. U.S. Pat. No. 6,106,861 discloses a rapidly disintegrable multiparticulate tablet which disintegrates in the mouth in less than 40 seconds and includes excipients selected from disintegrating agents, binding agents, and an active ingredient. The active ingredient is in the form of microcrystals coated with a taste masking coating that includes polymethacrylates and cellulose polymers such as hydroxypropyl-methyl cellulose, hydroxypropyl cellulose and cellulose acetophthalates. U.S. Pat. No. 6,136,347 describes flavor-masked pharmaceutical compositions that include microcapsules coated with water insoluble neutral methacrylic acid ester copolymers and triethylcitrate. PCT application WO 99/44581 discloses a process for taste masking of topiramate by coating the core with a taste masking coating mixture. The taste masking mixture includes cellulose acetate, cellulose acetate butyrate, methylcellulose, ethylcellulose or an Eudragit, and a disintegrant. U.S. 20060127479 to Kumaraperumal discloses a taste-masked drug coated with an acrylate polymer. U.S. 20060039981 to Murpani discloses a taste-masked drug coated with an acrylate polymer.
Acceptable taste-masking in orodispersible dosage forms is difficult to achieve, especially with a drug such as TOP, since it is more difficult to mask the taste of a high-dose drug in such a dosage form. It is not possible to predict a priori which taste-masked form of TOP will be suitable for use in an orodispersible dosage form, since the process and components used to prepare the orodispersible dosage form would very likely alter the taste-masked TOP thereby forming unmasked TOP during preparation of the dosage form. Moreover, it is not possible to predict a priori whether a particular taste-masked form of topiramate will retain its taste masking when incorporated into a three-dimensionally printed dosage form due to the use of various ingredients during printing and use of heat during drying.
None of the above discloses a taste-masked rapidly dissolving solid oral dosage form containing TOP as described herein. It would be beneficial to provide a taste-masked rapidly-dispersing orodispersible solid oral dosage form containing TOP that exhibits sufficiently low friability and sufficient hardness to withstand storage and handling while at the same time exhibiting an extremely rapid disintegration rate and acceptable taste; however, no such suitable dosage form containing TOP has been disclosed in the art. In particular, no such three-dimensionally printed dosage form has been disclosed.